Chemotherapy drugs for the treatment of cancer are generally directed to inhibiting the reproduction of malignant cells and killing malignant cells, thereby preventing tumor growth or reducing tumor size. Some of the most commonly used cancer chemotherapy drugs include alkylating drugs, anthracycline antibiotics, taxanes, alkaloids, and topoisomerase inhibitors.
Alkylating drugs are the oldest anti-cancer drugs and are used to treat many types of cancer. Alkylating drugs are typically methylating agents or chloroethylating agents which cause apoptosis in malignant cells. Temozolomide, (brand name, Temodar®, Schering-Plough Corp.), is an oral alkylating agent used in the treatment of brain cancer (1-3), e.g., glioblastoma multiforme and oligodendroglioma, and of melanoma (4, 5). It has also been used to treat prostate cancer, pancreatic carcinoma, soft tissue sarcoma, and renal cell carcinoma (6-12). Temozolomide inhibits cell reproduction by inhibiting DNA replication (13).
Temodar® has unique characteristics compared with other alkylating agents. For example, it is administered orally, forms a small lipophilic molecule that crosses the blood-brain barrier, is less toxic than other alkylating agents, does not chemically cross-link DNA, and is effective on a wide variety of cancers. However, although Temodar® is the current chemotherapeutic standard for treating brain tumors, as many as 50% of brain tumors are resistant to Temodar® therapy (14, 15). Resistance to Temodar® is also found in melanoma (16, 17).
Anthracycline antibiotics include doxorubicin, daunorubicin, epirubicin, idarubicin, valrubicin and are commonly used to treat most types of cancers, e.g., leukemias, Hodgkin's lymphoma, cancers of the bladder, breast, stomach, lung, ovaries, and thyroid, soft tissue sarcoma, multiple myeloma, and others. Doxorubicin acts by intercalating into DNA and preventing transcription and DNA synthesis (18). Doxorubicin is also a topoisomerase I inhibitor (19) and IIα poison (20).
Topoisomerase inhibiting drugs include doxorubicin, etoposide, and teniposide, and are generally used to treat leukemia, lung, ovarian, and gastrointestinal cancers (21, 22). These drugs act by inhibiting topoisomerase I or topoisomerase IIα or IIβ, thereby preventing DNA replication, recombination, transcription and chromosome segregation (23, 24).
Although these drugs are initially effective, tumor cells have, or may develop resistance to them. There are multiple mechanisms by which the cancer cells develop resistance to topoisomerase inhibitors. For example, endogenously produced ganglioside GM3 was shown to be involved in etoposide and doxorubicin resistance by up-regulating Bcl-2 expression in 3LL Lewis lung carcinoma cell line (25).
Primary non-malignant and malignant brain and central nervous system tumors are expected to occur in more than 64,000 people in the United States in 2011 (26). Gliomas represent 31% of all primary brain and central nervous system tumors, and over 80% of gliomas are malignant (26). The mortality rate of primary malignant brain and CNS tumors is high; approximately 22,020 new adult cases of brain and other nervous system cancers and 13,140 deaths occurred in 2010 (27). Malignant brain tumors account for 1.4% of all primary malignant cancers, and 2.2% of all cancer related deaths (28). Despite access to state-of-the-art surgical, radiation, and chemotherapies, survival rates for patients with newly diagnosed glioblastoma multiforme, the most common malignant glioma, was very poor. The median survival for GBM patients was 14.6 months and the 2 year survival of patients with GBM was 10.4% for radiotherapy alone and only 26.5% undergoing combined therapy treatment of Temodar® and radiation (29). The two to five year survival rate for malignant glioma has remained unchanged over the past 30 years. Thus, despite aggressive treatments, brain tumors generally recur, and are fatal.
Ovarian cancer is the second most common gynaecologic cancer, and represents the leading cause of gynecologic cancer-related death in Europe and United States (30, 31). It is estimated that 21,880 new cases and 13,850 deaths from ovarian cancer occurred in the United States in 2010 (27). Treatment of ovarian cancer is surgery and chemotherapy, and sometimes radiotherapy. Platinum based compounds are standard first-line agents for ovarian cancer and initial response rates are high (32). However, subsequent relapse with acquired platinum resistance is frequent and closely linked to the poor survival associated with this cancer.
Accordingly, a significant clinical need exists for additional chemotherapeutic agents that are toxic to a wide range of tumors and tumor cell types, in particular tumors and tumor cells that are resistant to current treatments such as radiotherapy, and resistant to other chemotherapeutic drugs. Therefore, in a first embodiment of the present invention it is an aim to provide solutions to meet this need.
There is also a continuing requirement, not only to provide treatments as described above, but to improve treatments for all forms of cancer. In other words, there is a clinical need for improved compounds and compositions for treating brain cancers, ovarian cancers as well as other cancers more generally. In a second embodiment it is an aim to provide further compounds and compositions for treating cancers generally, and brain and ovarian tumors specifically.
It has been known that barbituric acid derivatives have value as therapeutic agents for many years. In the past they have been employed for their central nervous system depressant activity, finding use inter alia as sedatives and anti-convulsants. Due to their toxicity, they have largely been replaced by benzodiazepines in such treatments.
However, more recently barbiturates have found new indications as potential treatments for a variety of diseases. For example, Ciustea et al. disclose inter alia barbiturates for treating the vaccinia virus (smallpox) (“Identification of non-nucleoside DNA synthesis inhibitors of vaccinia virus by high throughput screening”, J. Med. Chem., 51, 6563-6570, 2008).
Barbiturates have also been proposed as cancer treatments. For example, WO 01/93841 discloses certain barbituric acid analogues as therapeutic agents which inhibit HIF-1 activity. This may be used to treat proliferative conditions, such as cancer.
It is also known to use merocyanine dyes (compounds related to thiobarbiturates) to treat leukemia (WO 89/12080). This treatment involves the use of the dye to photosensitize leukemic cells, followed by exposure to light. Merocyanine 540 has also been shown to have apoptotic activity (Chen Yen-Chou et al., “Photodynamic anticancer agent merocyanine 540 inhibits cell growth by apoptosis”, Anticancer Research, 16, 5A, 2781-2788, 1996; D. L. Traul et al., “Induction of apoptosis and necrosis in leukemia and solid tumor cells by merocyanine 540-mediated PDT”, Photochemistry and Photobiology, 59, Spec. Issue, 70S, 1994; Shazib et al., “Caspase proteases mediate apoptosis induced by anticancer agent preactivated MC540 in human tumor cell lines”, Cancer Letters, 128, 1, 11-22, Jun. 5, 1998; Sieber et al., “Second generation merocyanine photosensitizers for photodynamic therapy”, Trends in Photochemistry & Photobiology, 10, 1-13, 2003).
Some barbiturate derivatives have been proposed as possible modulators of apoptosis and therefore possible anti-cancer agents (WO2011/094708). Several have been proposed as possible breast cancer and prostate cancer treatments (WO2009/065897). Further proposed activities include: as inhibitors of MALT1 proteolytic and/or autoproteolytic activity (WO2009/065897); as a RAD51 protein modulator to protect against DNA damage (WO2009/018219); as c-Rel activity inhibitors (WO2007/120842) for treating inter alia cancer; as Pin-1 modulators (WO2003/074497) for treating inter alia cancer; as potential cancer treatments when combined with indole (Palwinder et al., “Design, synthesis and anticancer activities of hybrids of indole and barbituric acid—identification of highly promising leads”, Bioorganic & Medicinal Chemistry Letters, 19, 11, 3054-3058, 2009); and as inhibitors decreasing the proliferation of cervix cancer cells (Shuangding et al., “Multidentate small-molecule inhibitors of vaccinia H1-related (VHR) phosphatase decrease proliferation of cervix cancer cells”, Journal of Medicinal Chemistry, 52, 21, 6716-6723, 2009).
However, to date, whilst some barbiturates and their analogues have received attention, none have been found which satisfactorily solve the problems underlying the present invention discussed above. The present inventors have surprisingly discovered a class of barbiturates and related compounds which may provide therapies, such as treatments for cancer, especially for cancers that are resistant to current drugs such as Temodar®, and for cancers that are resistant to radiation. These compounds may be used to improve treatments for all forms of cancer.